The present invention relates to a process for the preparation of low-peroxide crosslinked vinyllactam polymer by free-radical polymerization in the presence of at least one organic substance acting as antioxidant, and also low-peroxide crosslinked vinyllactam polymer obtainable by this process and its use.
Many oxidation-sensitive polymers such as crosslinked and uncrosslinked homo- and copolymers of N-vinylpyrrolidone are usually converted to pourable powders following their polymerization by spray-drying or drum-drying or another warm-air drying. In these processes, as a result of the intensive air contact and the heat, traces of peroxides are formed, the content of which increases still further in the course of the subsequent packaging, storage and handling. This tendency towards peroxide formation can present problems when using polymers such as polyvinylpyrrolidone (PVP and PVPP) in pharmaceutical preparations. In the current pharmacopeia, e.g. Ph. Eur. 6 and JP XIV, the peroxide content for these polymers is limited to a maximum of 400 ppm. Through drying with the exclusion of air, storage at low temperatures and/or the hermetically sealed packaging under vacuum or an inert gas, the kinetics of peroxide formation can indeed be slowed, but not prevented. In addition, these processes are associated with a very high expenditure, meaning that the acceptance of such measures by the user is low. Moreover, it is the wish of pharmaceutical manufacturers to obtain polymers with even lower peroxide quantities, for example not more than 100 or even not more than 50 ppm, it being the intention then that these values are reliably not reached even in the event of the longest possible storage period.
Bühler writes in his book “Polyvinylpyrrolidone—Excipients for Pharmaceuticals”, Springer, 2005, pages 33 and 34, that all types of povidones and crospovidones (“povidone” is the generic name for the soluble polyvinylpyrrolidone (PVP) in the pharmaceutical sector; “crospovidone” is the generic name for water-insolubly crosslinked PVP, which is also referred to as PVPP and polyvinylpyrrolidone-popcorn polymer) have a measurable growth in the peroxide content upon storage in the presence of atmospheric oxygen. This growth is reportedly particularly severe for the povidone with K value 90. Consequently, it is advisable to store products with these K values at low temperatures and/or hermetically sealed into aluminum-polyethylene double-layered film bags under a nitrogen atmosphere. Nevertheless, according to Bühler, the further increase in peroxide contents can only be slowed, but not stopped, thereby.
Moreover, such aluminum-polyethylene multi-layered film bags are very expensive, and the aluminum layer can be easily damaged, as a result of which they largely lose the protective effect against the penetration of oxygen.
Bühler also reports on the color change in aqueous solutions of PVP, especially after storage or heating, for example during sterilization: the resulting yellow to brown-yellow coloration results from the oxidation by means of atmospheric oxygen. According to Bühler, this can be avoided by adding suitable antioxidants to the polymer (after its polymerization). Bühler names cysteine and sodium sulfite as such antioxidants.
However, a disadvantage of adding such antioxidants is that the peroxides originating from the polymerization and also forming directly afterwards consume a larger amount of the antioxidants even upon their addition to the polymer and thus reduce the protection and the storage time. To compensate, relatively large amounts of antioxidant therefore have to be used.
The oxidation sensitivity of polymers such as PVP, the macroscopically visible and measurable effects of the oxidation and also proposed measures for containing and inhibiting the oxidation has been described in many publications (see for example Bühler in the publication detailed above; Kline in Modern Plastics, 1945, November, from page 157 onwards; Peniche et al. in Journal of Applied Polymer Science Vol. 50, pages 485-493, 1993; EP-B 873 130; U.S. Pat. No. 6,331,333; Encina et al. in the Journal of Polymer Science: Polymer Letters Edition, Vol. 18, pages 757 to 760).
Like this, U.S. Pat. No. 6,498,231 B2 describes the addition of antioxidants to the ready prepared polymer.
EP 1263813 B1 discloses a process for popcorn polymerization with adjustment of the particle size of the popcorn polymers by means of passing through a stream of inert gas and/or adding reducing agents. In this case, a reducing agent can optionally be added in amounts of from 0.1 to 1% by weight, based on the monomer mixture, for achieving full freedom from oxygen in the reaction mixture. The reducing agents described are sodium sulfite, sodium pyrosulfite, sodium dithionite, ascorbic acid or mixtures of the reducing agents. In the examples, sodium dithionite was used in an amount of 2.2*(10 to the power of −7) to 1.9% by weight, based on the monomer mixture.
A reduction in peroxide content or a stabilization against peroxide build-up is neither specified as the aim nor otherwise mentioned as such in the entire specification.
A process for stabilizing PVP by means of adding hydrazine and derivatives thereof is known from U.S. Pat. No. 2,821,519.
However, hydrazines are toxicologically unacceptable and undesired in N-vinylpyrrolidone homo- and copolymers and polymers of N-vinylpyrrolidone derivatives.
EP-B 1 083 884 describes a process for stabilizing polyvinylpyrrolidones against peroxide formation, in which aqueous solutions of the polymers are admixed with very small amounts of heavy metal salts or with peroxide-cleaving enzymes. These remain in the product. Suitable heavy metals are manganese, zinc, cobalt and in particular copper.
However, the use of the proposed heavy metals is disadvantageous on account of possible accumulation in the body. Moreover, the use of enzymes is disadvantageous for reasons of cost and stability.
GB 836,831 discloses a process for stabilizing polyvinylpyrrolidones against discolorations, in which solutions of the polymers are treated with sulfur dioxide, sulfurous acid or alkali metal sulfites.
It is known from DE-A 10 2005 005 974 that in the process known from GB 836,831, the peroxide build-up occurs after storage to an even greater extent than in the case of untreated polymers. DE-A 10 2005 005 974 therefore discloses a process in which the polyvinylpyrrolidones are treated firstly with sulfur dioxide, sulfurous acid or alkali metal salts thereof and then with a free-radical scavenger.
However, this process does not lead to the desired long-lasting effects with all polymers. For example, color and odor and peroxide content are not always satisfactory in the long term.
WO 2010/072640 discloses a process for the preparation of low-peroxide polymer comprising the treatment of the polymer with elemental metal in the presence of a liquid, and also a polymer obtainable by the process according to the invention with a peroxide content of less than 20 ppm based on the polymer solids content, where the peroxide content is determined two days after treatment by means of iodometry in accordance with Ph.Eur. 6, and the polymer has not more than 5 ppm, based on the polymer solids content, of any precious metal and not more than 1000 ppm, based on the polymer solids content, of any nonprecious metal.
Alkali metals which dissolve in the polymer solution or suspension with the formation of hydrogen are used, or precious metals and gaseous hydrogen which is passed over these precious metals. The hydrogen here is intended to reduce the peroxides.
The use of gaseous hydrogen and/or hydrogen-forming metals that are reactive with water is a safety risk which should not be underestimated in an industrial plant and therefore signifies higher costs.
Antioxidants are sufficiently known to the skilled person in all areas of polymer chemistry. Usually, therefore, antioxidants are added to oxidation-sensitive substances in order to protect these against further oxidation, possibly by atmospheric oxygen (see for example R. E. King III. “Antioxidants (Overview)” and S. Al-Malaika “Antioxidants and Stabilizers” in Polymeric Materials Encyclopedia, Volume 1, Ed. J. C. Salamone, 1996).
Such a procedure is described for example in DE10019470 for stabilizing polyvinylpyrrolidones. In this, antioxidants are added and mixed in after the polymerization or a post-treatment following the polymerization and before optionally drying to give polymer powders. The amounts required for this are given as 0.00001 to 30% by weight, based on the polymer solids content. Specifically mentioned amounts used in the examples are 0.1% by weight of hydroquinone and also 0.5 and 1% by weight of another antioxidant, in each case based on the polymer solids content.
It is common to this process and to all examples that the antioxidant is added in each case to a solution of a finished polymer, i.e. after the end of the polymerization or after a possible post-treatment of the polymer.
A disadvantage of the specified and specifically used substances from DE10019470 is that most of them are either not pharmaceutically suitable or are pharmaceutically suitable only to a very limited extent. Moreover, quite a few cause a sulfur odor or even react with customary drug active ingredients.
These substances likewise do not achieve an adequate reduction in peroxide content. In particular, no lowering, or only an inadequate lowering, of the peroxide values can be achieved with crosslinked, water-insoluble polymers.
U.S. Pat. No. 7,786,233 B2 discloses a polyvinylpyrrolidone composition with defined properties. In this connection, in order to achieve higher product stability, an antioxidant is added during heating before, during or after the pH adjustment, which is carried out following the acidic hydrolysis, which, for its part, is carried out when the polymerization and post-polymerization is complete. Peroxide contents were not determined. Crosslinked polymers such as, in particular, popcorn polymers and copolymers of vinylpyrrolidone, like other vinyllactam polymers as well, are not mentioned.
According to all of the procedures known to the skilled person, accordingly, antioxidants are added to the substance to be protected, for example a polymer, only after it has been prepared. According to the prior art publications, the addition thus takes place at a time at which the polymerization and the possible post-polymerization and post-treatment have been concluded. At this time, therefore, no unpolymerized monomers, or only very small residual contents, usually significantly less than 5% by weight, based on the total amount of monomers used, are present, If solid polymer is desired, then the addition of the antioxidant according to the prior art takes place in most cases directly before the drying.
U.S. Pat. No. 7,786,233 B2 already discloses, as the single known publication, the addition of antioxidant before, during or after the polymerization. However, the specification does not say any more about the action regarding “before” and “during” and also does not disclose any examples in this regard.
The organic substance acting as antioxidant within the context of this invention serves, according to the prior art, to protect oxidation-sensitive substances against oxidation. It therefore reacts with oxygen and other radicals and forms reaction products. In this process, the antioxidant is “consumed” as a result of the reaction with the radicals, as a result of which the amount of unconsumed antioxidant is continuously reduced further and therefore the protection against oxidation is also reduced.